With existing anti-tubercular therapies, treatment success rates for multi- and extensively-drug resistant tuberculosis (MDR-TB, XDR-TB) are dismal, highlighting the urgent need for new drugs. Gleevec (imatinib mesylate), a cancer drug used in humans for chronic myelogenous leukemia (CML) and gastrointestinal stromal tumors (GISTs), is a potential host- directed therapeutic (HDT) for drug resistant TB infections and HIV/TB co-infections. Gleevec inhibits c-Abl tyrosine kinase (TK), which is dys-regulated in CML, as well as related TKs (e.g. c-Kit). Gleevec is well tolerated, with few severe adverse events and little toxicity, especially at low doses. In animal models, Gleevec facilitates clearanc of Mycobacterium tuberculosis (Mtb), by disrupting the cellular mechanisms that Mtb uses for entry and survival in host cells, and stimulates emergency hematopoiesis, a host immune response to infection that mobilizes myeloid cell populations, but which is suppressed by Mtb. Gleevec acts synergistically with antibiotics, is effective against antibiotic-resistant mycobacteria, and may be less likely to engender resistance compared to antibiotics. Finally, Gleevec is also effective against other co-morbid infections such as HIV-1. Our proposal seeks to: (1) develop preclinical data on efficacy of Gleevec in a non-human primate (NHP) model of infection with TB and TB/SIV that mimic poorly controlled HIV/TB in humans; (2) determine safety and immunological responses at low doses in normal individuals in the United States, and in patients with previously treated pulmonary TB, including those infected with HIV; (3) determine the safety and microbiologic efficacy of Gleevec administered over 2 months to adults treated with optimized background MDR-TB regimens, including HIV-infected patients on ART. We will measure the time to sputum culture conversion, immunological parameters associated with myelopoeisis and pathogen-specific immune function. Deepak Kaushal (Tulane) will evaluate TB and TB/SIV infection for the UH2 portion. For the UH3, Daniel Kalman, (Emory), who has pioneered Gleevec as an HDT for infectious diseases including TB, and Edmund Waller (Emory), a hematologist, specializing in hematopoietic progenitor cell transplantation and immunotherapy, will evaluate the safety and immunologic effects (increased myelopoiesis) of low dose Gleevec in US subjects; Gregory P. Bisson (U. Penn), a TB immunologist who directs a clinical translational research unit in Botswana, will conduct dosing and safety studies in adults with treated pulmonary TB and a trial of Gleevec in adults with active MDR-TB, including those with HIV; and Tawanda Gumbo (Baylor), a pharmacometrician, will evaluate and model PK/PD parameters in normal and infected patient populations in the US and Botswana to guide dosing. Our experimental design will assess immunologic efficacy, toxicity, as well as pharmacology and drug interactions, and will evaluate microbiologic efficacy in patients with active MDR-TB. More broadly, these data will provide a paradigm with which to further evaluate Gleevec or other immunomodulatory HDTs as therapeutics for TB infection and HIV/TB co-infection.